title: The IL17A and IL17F loci have divergent histone modifications and are differentially regulated by prostaglandin E2 in Th17 cells.
abstract: Prostaglandin E2 (PGE2), IL-23 and IL-1β are implicated in inflammatory bowel disease susceptibility, likely in part by modulating IL-17 producing CD4(+) T helper (Th17) cells. To better understand how these three mediators affect Th17 cell memory responses, we characterized the gene expression profiles of activated human peripheral CD4(+) effector memory T cells and sorted Th17 memory cells from healthy donors concurrent with IL17A mRNA induction mediated by PGE2 and/or IL-23 plus IL-1β. We discovered that PGE2 and IL-23 plus IL-1β differentially regulate Th17 cytokine expression and synergize to induce IL-17A, but not IL-17F. IL-23 plus IL-1β preferentially induce IL-17F expression. The addition of PGE2 to IL-23 plus IL-1β only enhances IL-17A expression as mediated by the PGE2 EP4 receptor, and promotes a switch from an IL-17F to an IL-17A predominant immune response. The human Th17 HuT-102 cell line was also found to constitutively express IL-17A, but not IL-17F. We went on to show that the IL17A and IL17F loci have divergent epigenetic architectures in unstimulated HuT-102 and primary Th17 cells and are poised for preferential expression of IL17A. We conclude that the chromatin for IL17A and IL17F are distinctly regulated, which may play an important role in mucosal health and disease.
authors.affiliation: Department of Biological Sciences, Duquesne University, Pittsburgh, PA 15282, USA.
authors.forename: Juraj
authors.initials: J
authors.lastname: Adamik
authors.forename: Matthew
authors.initials: M
authors.lastname: Henkel
authors.forename: Anuradha
authors.initials: A
authors.lastname: Ray
authors.forename: Philip E
authors.initials: PE
authors.lastname: Auron
authors.forename: Richard
authors.initials: R
authors.lastname: Duerr
authors.forename: Arthur
authors.initials: A
authors.lastname: Barrie
mesh_terms: D002460:Cell Line; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D020381:Interleukin-17 / Q000235:genetics* / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D053759:Interleukin-23 / Q000378:metabolism; D011458:Prostaglandins E / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism*
chemical_list: D002843:Chromatin; D006657:Histones; C508717:IL17A protein, human; C440021:IL17F protein, human; D020381:Interleukin-17; D053583:Interleukin-1beta; D053759:Interleukin-23; D011458:Prostaglandins E; D012333:RNA, Messenger; D058309:Receptors, Prostaglandin E, EP4 Subtype; D000242:Cyclic AMP
keywords: 1-OH-PGE1; 1-hydroxy prostaglandin E1; C(T); ChIP; Chromatin; E prostanoid; EP; GWAS; IBD; IL-17A; IL-17F; PGE2; Prostaglandin E2; T helper; Th; Th17; chromatin immunoprecipitation; genome wide association studies; inflammatory bowel disease; prostaglandin E2; threshold cycle